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ACTINOMYCIN D IN THE TREATMENT OF TUMOURS
900 in the peripheral circulation, and an active phase in which the microfilarix accumulate in the lungs. This accumulation cannot depend on opening and shutting of the capillaries of the host: it must be an active response by the microfilarix themselves to some stimulus provided by the twenty-four-hour rhythm of the host; but the exact nature of this stimulus and indeed of many other factors concerned with microfilarial periodicity are still unknown. One aspect which particularly stirs the imagination is the distribution of the two forms of W. bancrofti-the periodic and the non-periodic-among the islands and atolls scattered over the vast waters of the Pacific Ocean. When the Polynesians migrated in their canoes from one island to another, they presumably took their parasites and their mosquitoes with them. The more easterly migrants, presumably the earlier ones, carried the non-periodic filaria which is transmitted by Aedes polynesiensis and Aed. pseudoscutellaris; the less easterly (or later) migrants carried the periodic nocturnal filaria which is transmitted by Culex fatigans. The two areas are divided by a line which approximates to longitude 170°E. East of this line the people are Polynesian, malaria is absent, and the filariasis is non-periodic. West of it the people are Melanesian, malaria prevails, and filariasis is nocturnal. Thus the distribution of their parasites helps to give information about the prehistoric migration of these mysterious and romantic peoples. ACTINOMYCIN D IN THE TREATMENT OF TUMOURS
anti-tumour agents (discussed in the symposium reported on p. 907), actinomycin is of special interest. First isolated in 1940 by Waksman and Woodruff from a culture of soil actinomyces (Streptomyces antibioticus), it was found to have a strong action against gram-negative organisms, but was also selectively cytotoxic to mammalian tissues. Although too toxic as a clinical antibiotic, it was reinvestigated for its potential anti-tumour effect. Closely related compounds, designated actinomycin A, B, C, D, I, J, and X, differing only in the composition of aminoacids in the peptide side-chain of the moleculewere soon isolated. Chemically, the various actinomycins are in fact mixtures of each other, and only actinomycin D is relatively pure.3 Actinomycin D was shown to act in mice against trans-
OF the
new
planted malignant melanoma,
mammary adenocarcinoma, and leukaemia at doses of 75-100 ug. per kg. bodyweight.4 Parenteral treatment is essential,5 and even administered parenterally the drug varies in its effect, although solutions of crystalline actinomycin D in 25% ethanol have proved stable for six weeks.5 Early clinical trials failed to show any benefit in children
leukxmia, but important temporary improveproduced in rhabdomyosarcoma, Wilm’s and tumour, Hodgkin’s disease.6 Moore et al.’ studied the effect of the drug in adults with various forms of advanced malignant disease. With total doses of 50-75 {jLg. per kg. body-weight intravenously, divided into five or ten daily injections, objective temporary tumour regression was observed in only 12 of 67 patients (carcinoma of the breast 3, lymphosarcoma 3, carcinoma of stomach 1, melanoma 1, miscellaneous 4) and only 3 of these patients S. A., Woodruff, H. B. Proc. Soc. exp. Biol., N.Y. 1940, 45, 609. 1. Waksman, 2. Pugh, L. H., Katz, E., Waksman, S. A. J. Bact. 1956, 72, 660. with
ment
acute
was
3. Waksman, S. A., Katz, E., Vining, L. J. Path. Bact. 1958, 44, 602. 4. Farber, S. Amer. J. Path. 1955, 31, 582.
DiPaolo, J. A., Moore, G. E., Niedbala, T. F. Cancer Res. 1957, 17, 1127. Farber, S., Toch, R., Sears, E. M., Pinkel, D. Advanc. Cancer Res. 1956, 4, 49. 7. Moore, G. E., DiPaolo, J. A., Kondo, T. Cancer, 1958, 11, 1204.
5.6.
lasting more than a month. On the other cells disappeared from the blood, even masses remained unchanged. Slight depression on the fourth to twenty-fourth day
had remissions
hand, when
tumour tumour
marrow
third of the patients, but usually recovered spontaneously within ten days. Other untoward effects included anorexia, nausea, vomiting, diarrhoea, buccal ulceration, acne, alopecia, an enhanced tumour growth-rate after ineffective therapy, and thrombophlebitis at the site of injection. (Excessive skin reactions over previously irradiated areas have also been reported.8) Maintenance therapy did not appear to be of benefit. Tan et al.8 at the Sloan-Kettering Institute have now reported their experience with actinomycin D in 111 children with metastatic cancer. Striking regression of massive pulmonary metastases occurred in several patients. The drug appeared to potentiate the predicted response to radiotherapy in 28 of 50 patients treated with approximately 50% of the estimated therapeutic dose of X rays, even in some relatively radioresistant tumours. Particularly interesting are the 49 children treated with actinomycin D alone, in 16 of whom objective tumour regression was attributable solely to the drug. In a 2-year-old boy with a Wilm’s tumour a pulmonary metastasis regressed completely, and he has had no further recurrence for two years. In all, 6 of 16 children with metastatic Wilm’s tumour who received actinomycin D alone showed objective improvement; indeed, Tan et al. suggest that this should be the initial form of therapy in such cases, with additive radiotherapy only if tumour regression is incomplete. Experience with other tumours was less favourable, although temporary benefit was observed in some cases of neuroblastoma, rhabdomyoSimilar sarcoma, lymphadenoma and bone sarcoma. results were reported by Pinkel9 in a smaller series, in which objective temporary improvement in rhabdomyosarcoma and Wilm’s tumour was also recorded. A 31/2year-old girl with a recurrent rhabdomyosarcoma of the face had a particularly gratifying response, pronounced tumour shrinkage making a radical excision possible. Although tumour inhibition with oral therapy could not be shown experimentally,5 the Sloan-Kettering group, using oral doses of 3 to 10 mg. daily, estimated from the systemic effects that about 5% was absorbed. But the toxic effects on the gastrointestinal tract were more severe and commoner, preventing adequate therapy by this means. The recommended total intravenous dose is 75 (Lg. per kg. body-weight or 2-3 mg. per sq. m. body surface in three to six injections over a period of one to two weeks; but repeated courses may be needed in the absence of a suitable preparation for maintenance therapy. The evidence suggests that actinomycin D may have a useful place in the treatment of disseminated Wilm’s tumour and other metastatic sarcomas in children. Tumour shrinkage may make surgical excision possible; secondary deposits may regress following removal of the primary growth; and the effect of radiotherapy may be after the
start
of
treatment was
noted in
a
potentiated. We regret to announce the death on Nov. 14 at Bungay, of Mr. HAROLD WILSON, consulting surgeon to St. Bartholomew’s Hospital, London. Sir FRANCIS PRIDEAUX, Ministry of Pensions, died 8. 9.
formerly director-general of the on
Nov. 15
at
the age of 75.
Tan, C. T. C., Dargeon, H. W., Burchenal, J. H. Pediatrics, 1959, 24, 544. Pinkel, D. ibid. 1959 23, 342.
anti-tumour agents (discussed in the symposium reported on p. 907), actinomycin is of special interest. First isolated in 1940 by Waksman and Woodruff from a culture of soil actinomyces (Streptomyces antibioticus), it was found to have a strong action against gram-negative organisms, but was also selectively cytotoxic to mammalian tissues. Although too toxic as a clinical antibiotic, it was reinvestigated for its potential anti-tumour effect. Closely related compounds, designated actinomycin A, B, C, D, I, J, and X, differing only in the composition of aminoacids in the peptide side-chain of the moleculewere soon isolated. Chemically, the various actinomycins are in fact mixtures of each other, and only actinomycin D is relatively pure.3 Actinomycin D was shown to act in mice against trans-
OF the
new
planted malignant melanoma,
mammary adenocarcinoma, and leukaemia at doses of 75-100 ug. per kg. bodyweight.4 Parenteral treatment is essential,5 and even administered parenterally the drug varies in its effect, although solutions of crystalline actinomycin D in 25% ethanol have proved stable for six weeks.5 Early clinical trials failed to show any benefit in children
leukxmia, but important temporary improveproduced in rhabdomyosarcoma, Wilm’s and tumour, Hodgkin’s disease.6 Moore et al.’ studied the effect of the drug in adults with various forms of advanced malignant disease. With total doses of 50-75 {jLg. per kg. body-weight intravenously, divided into five or ten daily injections, objective temporary tumour regression was observed in only 12 of 67 patients (carcinoma of the breast 3, lymphosarcoma 3, carcinoma of stomach 1, melanoma 1, miscellaneous 4) and only 3 of these patients S. A., Woodruff, H. B. Proc. Soc. exp. Biol., N.Y. 1940, 45, 609. 1. Waksman, 2. Pugh, L. H., Katz, E., Waksman, S. A. J. Bact. 1956, 72, 660. with
ment
acute
was
3. Waksman, S. A., Katz, E., Vining, L. J. Path. Bact. 1958, 44, 602. 4. Farber, S. Amer. J. Path. 1955, 31, 582.
DiPaolo, J. A., Moore, G. E., Niedbala, T. F. Cancer Res. 1957, 17, 1127. Farber, S., Toch, R., Sears, E. M., Pinkel, D. Advanc. Cancer Res. 1956, 4, 49. 7. Moore, G. E., DiPaolo, J. A., Kondo, T. Cancer, 1958, 11, 1204.
5.6.
lasting more than a month. On the other cells disappeared from the blood, even masses remained unchanged. Slight depression on the fourth to twenty-fourth day
had remissions
hand, when
tumour tumour
marrow
third of the patients, but usually recovered spontaneously within ten days. Other untoward effects included anorexia, nausea, vomiting, diarrhoea, buccal ulceration, acne, alopecia, an enhanced tumour growth-rate after ineffective therapy, and thrombophlebitis at the site of injection. (Excessive skin reactions over previously irradiated areas have also been reported.8) Maintenance therapy did not appear to be of benefit. Tan et al.8 at the Sloan-Kettering Institute have now reported their experience with actinomycin D in 111 children with metastatic cancer. Striking regression of massive pulmonary metastases occurred in several patients. The drug appeared to potentiate the predicted response to radiotherapy in 28 of 50 patients treated with approximately 50% of the estimated therapeutic dose of X rays, even in some relatively radioresistant tumours. Particularly interesting are the 49 children treated with actinomycin D alone, in 16 of whom objective tumour regression was attributable solely to the drug. In a 2-year-old boy with a Wilm’s tumour a pulmonary metastasis regressed completely, and he has had no further recurrence for two years. In all, 6 of 16 children with metastatic Wilm’s tumour who received actinomycin D alone showed objective improvement; indeed, Tan et al. suggest that this should be the initial form of therapy in such cases, with additive radiotherapy only if tumour regression is incomplete. Experience with other tumours was less favourable, although temporary benefit was observed in some cases of neuroblastoma, rhabdomyoSimilar sarcoma, lymphadenoma and bone sarcoma. results were reported by Pinkel9 in a smaller series, in which objective temporary improvement in rhabdomyosarcoma and Wilm’s tumour was also recorded. A 31/2year-old girl with a recurrent rhabdomyosarcoma of the face had a particularly gratifying response, pronounced tumour shrinkage making a radical excision possible. Although tumour inhibition with oral therapy could not be shown experimentally,5 the Sloan-Kettering group, using oral doses of 3 to 10 mg. daily, estimated from the systemic effects that about 5% was absorbed. But the toxic effects on the gastrointestinal tract were more severe and commoner, preventing adequate therapy by this means. The recommended total intravenous dose is 75 (Lg. per kg. body-weight or 2-3 mg. per sq. m. body surface in three to six injections over a period of one to two weeks; but repeated courses may be needed in the absence of a suitable preparation for maintenance therapy. The evidence suggests that actinomycin D may have a useful place in the treatment of disseminated Wilm’s tumour and other metastatic sarcomas in children. Tumour shrinkage may make surgical excision possible; secondary deposits may regress following removal of the primary growth; and the effect of radiotherapy may be after the
start
of
treatment was
noted in
a
potentiated. We regret to announce the death on Nov. 14 at Bungay, of Mr. HAROLD WILSON, consulting surgeon to St. Bartholomew’s Hospital, London. Sir FRANCIS PRIDEAUX, Ministry of Pensions, died 8. 9.
formerly director-general of the on
Nov. 15
at
the age of 75.
Tan, C. T. C., Dargeon, H. W., Burchenal, J. H. Pediatrics, 1959, 24, 544. Pinkel, D. ibid. 1959 23, 342.